The invention relates to xcex2-alanine derivatives of the formula I 
in which
Q1, Q2,
Q3 or Q4 is, in each case, independently of one another, CH or N,
R1 is H, A, Ar, Hal, OH, OA, CF3 or OCF3,
R2 is H or A, 
R4 and R5 are, in each case independently of one another H, A, Hal, OH, OA, CF3, OCF3, CN, NH2, NHA, NA2 or NHxe2x80x94C (O) A,
R6 is H, A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C (O) A or xe2x80x94(CH2)mxe2x80x94Ar,
A is alkyl with 1 to 6 C atoms,
Ar is unsubstituted or mono-, di- or trisubstituted aryl,
Hal is F, Cl, Br or I,
n is 2, 3, 4, 5 or 6,
m is 1, 2, 3 or 4,
and their physiologically acceptable salts and solvates.
Partly similar compounds are disclosed in WO 97/26250 or WO 97/24124.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, in particular inhibiting the interactions with the xcex1"ugr"xcex23 or xcex1"ugr"xcex25 integrin receptors with ligands such as, for example, the binding of vitronectin to the xcex1"ugr"xcex23 integrin receptor. Integrins are membrane-bound, heterodimeric glycoproteins which consist of an xcex1 subunit and of a smaller. xcex2 subunit. The relative affinity and specificity for ligand binding is determined by the combination of the various xcex1 and xcex2 subunits. The compounds according to the invention show particular activity in the case of the integrins xcex1"ugr"xcex21, and xcex1"ugr"xcex23, xcex1"ugr"xcex25, xcex1IIbxcex23, and xcex1"ugr"xcex26 and xcex1"ugr"xcex28, preferably of xcex1"ugr"xcex23 and xcex1"ugr"xcex25. In particular, potent selective inhibitors of the integrin xcex1"ugr"xcex23 have been found. The xcex1"ugr"xcex23 integrin is expressed on a number of cells, for example endothelial cells, smooth vascular muscle cells, for example of the aorta, cells for breaking down bone matrix (osteoclasts) or tumour cells.
The effect of the compounds according to the invention can be detected, for example, by the method described by J. W. Smith et al., in J. Biol. Chem. 1990, 265, 12267-12271. The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P. C. Brooks, R. A. Clark, and D. A. Cheresh in Science 1994, 264, 569-571.
The possibility of inhibiting this interaction and thus for inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfield, T. Hu, G. Klier and D. A. Cheresh in Cell 1994, 79, 1157-1164. Descriptions are given therein of, for example, xcex1"ugr"xcex23 antagonists or antibodies against xcex1"ugr"xcex23 which bring about shrinkage of tumours through induction of apoptosis.
The experimental demonstration that the compounds according to the invention also prevent adhesion of living cells to the appropriate matrix proteins, and accordingly, also prevent the adhesion of tumour cells to matrix proteins can be provided in a cell adhesion test in analogy to the method of F. Mitjans et al., Cell Science 1995, 108, 2825-2838.
The compounds of the formula I are able to inhibit the binding of metalloproteinases to integrins and thus prevent the cells being able to utilize the enzymatic activity of the proteinase. One example is to be found in the ability to inhibit the binding of MMP-2 (matrix metalloproteinase 2) to the vitronectin receptor xcex1"ugr"xcex23 by a cylcic RGD peptide, as described in P. C. Brooks et al., Cell 1996, 85, 683-693.
Compounds of the formula I which block the interaction of integrin receptors and ligands such as, for example, of fibrinogen on the fibrinogen receptor (glycoprotein IIb/IIIa) prevent, as antagonists, the spread of tumour cells by metastasis and can therefore be employed as substances with antimetastatic activity in operations in which the tumours are surgically removed of dealt with. This is demonstrated by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place by the formation of microaggregates (microthrombi) through the interaction of the tumour cells with blood platelets. The tumour cells are shielded by the protection in the microaggregate and are not recognized by the cells of the immune system. The microaggregates are able to attach to vessel walls, which facilitates further penetration of tumour cells into the tissue. Since the formation of microthrombi is mediated by a ligand binding to the corresponding integrin receptors, for example xcex1"ugr"xcex23 or xcex1IIbxcex23, on activated blood platelets, the appropriate antagonists can be regarded as effective metastasis inhibitors.
The compounds of formula I can be employed as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and/or therapy of circulatory disorders, thrombosis, myocardial infarct, arteriosclerosis, stroke, angina pectoris, tumorous disorders such as tumour development or tumour metastasis, osteolytic diseases such as osteoporosis, diseases with pathological angiogenesis, such as, for example, inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn""s disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing to assist the healing process.
The compounds of the formula I can be employed as substances with antimicrobial activity in operations where biomaterials, implants, catheters or heart pacemakers are used.
They moreover have an antiseptic effect. The antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 1988, 2851-2855.
Selected compounds of the formula I are, in particular, selective xcex1"ugr"xcex23 and xcex1"ugr"xcex26 integrin receptor inhibitors.
Selected compounds of the formula I are, in particular, selective xcex1"ugr"xcex25 and xcex1"ugr"xcex26 integrin receptor inhibitors. Selected compounds of the formula I are, in particular, selective xcex1"ugr"xcex23 and xcex1"ugr"xcex25 and xcex1"ugr"xcex25 integrin receptor inhibitors.
The effect of a compound on an xcex1"ugr"xcex25 integrin receptor and thus the activity as inhibitor can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271. The effect of a compound on an xcex1"ugr"xcex76 integrin receptor and thus the activity as inhibitor can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.
These selected compounds are particularly suitable for therapy or for controlling pathological processes which can be influenced by the integrins xcex1"ugr"xcex23 and/or xcex1"ugr"xcex25 and xcex1"ugr"xcex26 . Examples of angiogenic pathologies are skin disorders such as psoriasis, bullous pemphigus, dermatitis and erythemas, as well as pulmonary fibrosis, cystic fibrosis, endometriosis, cirrhosis or the liver of periodontitis, and they can be influenced through xcex1"ugr"xcex23 and/or xcex1"ugr"xcex25 inhibitors, and pathologies of epithelial cells which can be influenced through xcex1xcexcxcex26 inhibitors are, in particular, carcinomas and the abovementioned skin disorders and pulmonary fibrosis (Lit.: Healy D. L. et al., Hum. Reprod. Update 1998, 4 (5), 736-40; Creamer D. et al., Br. J. Dermatol. 1997, 137, 851-5; Norrby K., APMIS, 1997, 105, 417-37; Creamer D. et al., Br. J. Dermatol. 1997, 136, 859-65; Polverini P. J., Crit. Rev. Oral. Biol. Med, 1995, 6, 230-47; Brown L. F. et al., J. Invest. Dermatol. 1995, 104, 744-9; Hoyt D. G. et al., Am. J. Physiol., 1997, 273, L612-7; Pilewski J. M. et al., ibid 1997, 273, L256-63 or Goldman M. et al., Gene. Ther. 1996, 3, 811-8).
A preferred use of these selected compounds is in cancer therapy.
Approaches to solutions for cancer therapy usually concentrate on controlling a part-region, a compartment, in the development of a solid tumour. Compartments are, inter alia, the development of the tumour per se or the blood vessels growing into the tumour, which are responsible for the supply of nutrients to the tumour. As soon as the supply of nutrients to the tumour is restricted, the production and secretion of polypeptide growth factors are induced by transcriptional activators, usually via hypoxic or hypoglycaemic promoters. These factors activate the sprouting of blood vessels. In order for the endothelial cells of the blood vessel to be able to divide, anti-apoptotic signals are necessary and are released by cell surface receptors and the integrin family. The integrin receptors xcex1"ugr"xcex23 and xcex1"ugr"xcex25 are particularly responsible for this release (Lit.: P. C. Brooks, Eur. J. Cancer, 1996, 32A, 2423-2429; P. C. Brooks et al., Cell, 1994, 79, 1157-1164).
Inhibitions of these integrin receptors xcex1"ugr"xcex23 and/or xcex1"ugr"xcex25, in particular of xcex1"ugr"xcex23, induces apoptosis of the activated endothelial cells of the blood vessel growing into the tumour, while the normal vascular bed, which is at rest, remains in tact. The tumour loses its supply of nutrients, and thus its development is stopped. The tumour per se, that is to say the degenerate cancer cells are, however, not impaired by this therapeutic approach, so that growth of the tumour can start again after the treatment ceases.
The integrin receptors on the surface of tumour cells differ significantly from those expressed on normal tissue. For example, high de novo expression of the rare integrin xcex1"ugr"xcex26 is found on many carcinomas, whereas xcex1"ugr"xcex23 is a good marker for progressive malignant melanomas. It is also known that xcex1"ugr"xcex26 is involved in the mechanisms of actual tumour development and in the mechanisms of the invasion of healthy tissue by degenerate cells, metastasis.
A combined therapy aimed both at the angiogenesis of the tumour tissue and at controlling the tumour tissue per se has to date been described only through the combined use of xcex1"ugr"xcex23 integrin inhibitors with cytotoxic substances (chemotherapy) or by irradiation (radiotherapy).
It has been found, surprisingly, that the use of selective xcex1"ugr"xcex23integrin inhibitors and the use of selective xcex1"ugr"xcex26 integrin inhibitors is suitable for producing a pharmaceutical for such a combined therapy. A synergistic effect is observed. The high selectivity of the inhibition of the xcex1"ugr"xcex23 and xcex1"ugr"xcex26 integrin receptors means that there is no further inhibition of other integrinsxe2x80x94such as, for example, xcex15xcex21 or xcex1IIbxcex23, which have important and critical functions for example in normal tissue.
It has also been found that the use of selective xcex1"ugr"xcex25 integrin inhibitors and the use of selective xcex1"ugr"xcex26 integrin inhibitors is likewise suitable for producing a pharmaceutical for such a combined therapy, as well as the combined use of selective xcex1"ugr"xcex23, xcex1"ugr"xcex25 and xcex1"ugr"xcex26 integrin inhibitors. A synergistic effect is observed in each case.
The compounds of the formula I have at least one chiral centre and can therefore occur in several stereoisomeric forms. All these forms (for example D and L forms) and mixtures thereof (for example the DL forms) are included in the formula.
The compounds of the invention also include so-called prodrug derivatives, that is to say compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention. It is also possible for free amino groups or free hydroxy groups or substituents of compounds of the formula I to be provided with appropriate protective groups.
Solvates of the compounds of the formula I mean adducts of inert solvent molecules with the compounds of the formula I, which are formed because of their mutual attractions. Examples of solvates are mono- or dihydrates or addition compounds with alcohols, such as, for example, with methanol or ethanol.
The invention relates to the compounds of formula I and their salts and solvates and to a process for preparing compounds of the formula I and their salts and solvates, characterized in that
(a) a compound of the formula II 
in which Q1, Q2, Q3, Q4, R1 and n have the meanings stated in claim 1, is reacted with a compound of the formula III 
in which R2, R3, R4, R5 and R6 have the meanings stated in claim 1, and where appropriate, the radical R6xe2x89xa0H is converted in to the radical R6=H,
(b) a compound of the formula IV 
in which Q1, Q2, Q3, Q4, R1, and R2 and n have the meanings stated in claim 1, is reacted with a compound of the formula V 
in which R3, R4, R5 and R6 have the meanings stated in claim 1, and where appropriate, the radical R6xe2x89xa0H is converted into the radical R6=H,
or
(c) one or more radicals R1, R2, R3, R4 and/or R5 in a compound of the formula I are converted into one or more radicals R1, R2, R3, R4 and/or R5 by, for example,
i) alkylating a hydroxyl group,
ii) hydrolyzing an ester group to a carboxyl group,
iii) esterifying a carboxyl group,
iv) alkylating an amino group or
v) acylating am amino group,
and/or a basic or acidic compound of the formula I is converted by treatment with an acid or base into one of its salts or solvates.
In the above formulae, A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6, C atoms. A is preferably methyl, also ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, in addition pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. A is particularly preferably methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.
Ar is aryl which is unsubstituted or mono-, di- or trisubstituted by A, CF3, OH, OA, OCF3, CN or NO2 or Hal, with aryl being phenyl, naphthyl, anthryl or biphenylyl. Ar is preferably phenyl or naphthyl each of which is unsubstituted or mono-, di- or trisubstituted by A, CF3, OH, OA, OCF3, CN or NO2 or Hal.
Ar is therefore preferably phenyl, o-, m- or p-methyl-phenyl, o-, m- or p-ethylphenyl, o-, m- or p-propyl-phenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o- , m- or p-ethoxyphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, also preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5- , 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl or 3-chloro-4-fluorophenyl, 4-fluoro-2-hydroxyphenyl, naphthalen-1-yl, naphthalen-2-yl or 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-fluoronaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-hydroxynapthalen-1-yl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-methylnaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7-, 8-ethylnaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalen-2yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-fluoronaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-hydroxynaphthalen-2yl. Ar is very particularly preferably phenyl, o-, m- or p-fluorophenyl, m- or p-chlorophenyl, p-methylphenyl, p-trifluoromethylphenyl, 3--chloro-4-fluorophenyl, 4-fluoro-2-hydroxyphenyl, naphthalen-1-yl or naphthalen-2-yl.
Ar in xe2x80x94(CH2)mxe2x80x94Ar has one of the preferred meanings stated above, it being possible for m to 1 or 2. Benzyl is particularly preferred for xe2x80x94(CH2)mxe2x80x94Ar.
It is possible in xe2x80x94(CH2)mxe2x80x94OH for m to be 1, 2, 3 or 4. xe2x80x94(CH2)mxe2x80x94OH is preferably hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl, very particularly preferably hydroxyethyl.
A in xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A has one of the preferred meanings stated above, it being possible for m to be 1 or 2. It is particularly preferred for A to be tert-butyl and m to be 1.
Hal is preferably F, Cl or bromine.
n is 2, 3, 4, 5 or 6, particularly preferably 3, 4 or 5.
is preferably 3-(trifluoromethoxy)- or 4-(trifluoro-methoxy)phenyl. 
is preferably biphenyl-4-yl, 4xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-fluorobiphenyl-3-yl, 3xe2x80x2-fluorobiphenyl-4-yl, 2xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-chlorobiphenyl-4-yl, 3xe2x80x2-chlorophenyl-4-yl, 4xe2x80x2-methylbiphenyl-4-yl, 4xe2x80x2-(trifluoromethyl)biphenyl-4-yl, 3xe2x80x2-chloro-4xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-fluoro-2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-3-yl, 4-(naphthalen-1-yl)phenyl, 4-(naphthalen-2-yl)phenyl or 4-(naphthalen-1-yl)-3-hydroxyphenyl. 
is preferably, 2-, 3- or 4-nitrophenyl, 4-methyl-3-nitrophenyl, 4-chloro-3-nitrophenyl, 3-nitro-2-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.
Q1, Q2, Q3 or Q4 are each, independently of one another, CH or N. Q1 is preferably CH or N, Q2 is preferably CH, Q3 is preferably CH and Q4 is preferably CH. It is very particularly preferred for Q1, Q2, Q3 and Q4 to be CH.
R1 is H, A, Ar, Hal, OH, OA, CF3 or OCF3, where A, Ar or Hal have the preferred or particularly preferred meanings stated above. R1 is preferably H or A. The preferred positions for the substituents R1 are position 4 or 6. Position 4 on the ring system [lacuna] particularly preferred.
R2 is preferably H or A, particularly preferably H.
R3 is 
where R4 and R5 are, independently of one another, H, A, Hal, OH, OA, CF3, OCF3, CN, NH2, NHA, NA2 or NHxe2x80x94C(O)A, and AR has one of the meanings stated above.
R4 is particularly preferably H, A, OH or Hal.
R5 is particularly preferably H or OH.
R4 and R5 are particularly preferably H in 
It is particularly preferred for R4 to be H or OH and Ar to be phenyl which is unsubstituted or mono- or disubstituted by Hal, A or CF3, or unsubstituted naphthyl is 
It is particularly preferred for R4 to be H, A or Hal and R5 to be H or OH in 
R3 is preferably 2-, 3- or 4-trifluoromethoxyphenyl, 2-, 3- or 4-nitrophenyl, biphenyl-3-yl, biphenyl-4-yl, 3-methyl-, 4-methyl-, 5-methyl- or 6-methyl-2-(trifluoromethoxy)phenyl, 3-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-2-(trifluoromethoxy)phenyl, 2-methyl-, 4-methyl-, 5-methyl- or 6-methyl-3-(trifluoromethoxy)-phenyl, 2-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-3-(trifluoromethoxy)phenyl, 2-methyl-, 3-methyl-, 3-methyl-, 5-methyl- or 6-methyl-4-(trifluoromethoxy)phenyl, 2-ethyl-, 3-ethyl-, 5-ethyl- or 6-ethyl-4-(trifluoromethoxy)phenyl, 3-methyl-, 4-methyl-, 5-methyl- or 6-methyl-2-nitrophenyl, 3-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-2-nitrophenyl, 2-methyl-, 4-methyl-, 5-methyl- or 6-methyl-3-nitrophenyl, 2-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-3-nitrophenyl, 2-methyl-, 3-methyl-, 5-methyl- or 6-methyl-4-nitrophenyl, 2-ethyl-, 3-ethyl-, 5-ethyl- or 6-ethyl-4-nitrophenyl, 3-chloro-, 4-chloro-, 5-chloro- or 6-chloro-2-nitrophenyl, 2-chloro-, 4-chloro-, 5-chloro- or 6-chloro-3-nitrophenyl, 2-chloro-, 3-chloro-, 5-chloro- or 6-chloro-4-nitrophenyl, 3-nitro-2-hydroxyphenyl, 3-bromo-6-hydroxy-5-nitrophenyl, 4xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-fluorobiphenyl-3-yl, 3xe2x80x2-fluoro-biphenyl-4-yl, 2xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-chloro-biphenyl-4-yl, 3xe2x80x2-chlorobiphenyl-4-yl, 4xe2x80x2-methyl-biphenyl-4-yl, 4xe2x80x2-(trifluoromethyl)biphenyl-4-yl, 3xe2x80x2-chloro-4xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-fluoro-2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-3-yl, 4-(naphthalen-1-yl)phenyl, 4-(naphthalen-2-yl)phenyl or 4-(naphthalen-1-yl)-3-hydroxyphenyl.
Particularly preferred meanings for R3 are 4-(trifluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, biphenyl-4-yl, 4-methyl-3-nitrophenyl, 4-fluoro-2-hydroxyphenyl or 4-chloro-3-nitrophenyl, 4xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-fluorobiphenyl-3-yl, 3xe2x80x2-fluorobiphenyl-4-yl, 2xe2x80x2-fluorobiphenyl-4-yl, 4xe2x80x2-chlorobiphenyl-4-yl, 3xe2x80x2-chlorobiphenyl-4-yl, 4xe2x80x2-methylbiphenyl-4-yl, 4xe2x80x2-(trifluoromethyl)biphenyl-4-yl, 3xe2x80x2-chloro-4xe2x80x2-fluoro-biphenyl-4-yl, 4xe2x80x2-fluoro-2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-4-yl, 4xe2x80x2-fluoro-2xe2x80x2-hydroxybiphenyl-3-yl, 4-(naphthalen-1-yl)phenyl, 4-(naphthalen-2-yl)phenyl or 4-(naphthalen-1-yl)-3-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.
R6 is H, A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar, where A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar have one of the preferred or particularly preferred meanings stated above.
Compounds of the formula I in which R6 is preferably A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar, and their solvates, are so-called prodrugs, that is to say they are inactive in in vitro tests because they mask the biologically active carboxyl group. However, prodrugs are converted metabolically in the body into the biologically active form. The corresponding free acid which corresponds to a compound of the formula I with R6xe2x95x90H, and its salts and solvates, is active in vitro.
Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings stated hereinbefore. Some preferred groups of compounds can be expressed by the following part-formulae Ia to Ik which correspond to formula I and in which the undefined radicals have the meaning stated for formula I, but in which
in Ia 
In Ib 
In Ic 
In Id Q1, Q2, Q3 and Q4 of the formula I are CH. 
In Ie Q1 is N and Q2, Q3 and Q4 of the formula I are CH. 
In If R1 is H or A and 
In Ig R1 is H or A, 
and
Q1 is N and Q2, Q3 and Q4 are CH. 
In Ih R1 is H or A,
Q1, Q2, Q3 and Q4 are CH and 
In Ii R1 is H or A and 
In Ik R1 is H or A and 
Particularly preferred compounds of the formula Ia are
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-(trifluoromethoxyphenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid or
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid and their physiologically acceptable salts and solvates.
Particularly preferred compounds of the formula Ib are
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)-butyrylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridin-2-ylamino)-pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(2-nitrophenyl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(2-nitrophenyl)propionic acid,
3-(2-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid, methyl 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionate,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidin-2-ylamino)butyrylamino]acetylamino}propionic acid or
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
and their physiologically acceptable salts and solvates.
Particularly preferred compounds of the formula Ic are
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-(pyrimidin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[4-(pyrimidin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid or
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid and their physiologically acceptable salts and solvates.
Particularly preferred compounds of the formula Id are
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid,
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(2-nitrophenyl)-3-{2-[5-pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(2-nitrophenyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(2-nitrophenyl)propionic acid,
3-(2-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(6-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid,
methyl 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(6-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-(4-chloro-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
and their physiologically acceptable salts and solvates.
Preferred compounds of the formula Ie are
3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyrimidin-2-ylamino)butyrylamino]acetylamino}propionic acid,
3-(4-methyl-3-nitrophenyl)-3-{2-[5-(pyrimidin-2-ylamino)pentanoylamino]acetylamino}propionic acid,
3-{2-[5-(pyrimidin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid or
3-{2-[4-(pyrimidin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
and their physiologically acceptable salts and solvates.
Preferred compounds of the formula If are
3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
3-{2-[5-pyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-biphenylyl)propionic acid or
3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-biphenylyl)propionic acid,
and their physiologically acceptable salts and solvates.
The compounds of the formula I according to claim 1 and the starting materials for preparing them are moreover prepared by methods which are known per se and are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditions known and suitable for the said reactions. It is moreover possible to make use of variants which are known per se but are not detailed here.
The starting materials can, if required, also be formed in situ, so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I according to claim 1.
It is also possible for a plurality ofxe2x80x94identical or differentxe2x80x94protective amino and/or hydroxyl groups to be present in the molecular of the starting material. If the protective groups which are present differ from one another, they can in many cases be cleaved off selectively (compare in this connection: T. W. Greene, P. G. M. Wuts, Protective groups in Organic Chemistry, 2nd edition, Wiley, New York 1991 or P. J. Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgartxe2x80x94New York, 1994, H. Kunz, H. Waldmann in Comprehensive Organic Synthesis, Vol. 6 (ed. B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon, Oxford, 1991, pp. 631-701).
The term xe2x80x9camino protective groupxe2x80x9d is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions. Typical groups of this type are, in particularly, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the required reaction (or sequence of reactions), their nature and size is otherwise not critical; however, those with 1-20, in particular 1-8, C atoms are preferred. The term xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; alkenyloxycarbonyl such as allyloxycarbonyl (Aloc), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2-(phenylsulfonyl)ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protective groups are BOC, Fmoc and Aloc, also CBZ, benzyl and acetyl.
The term xe2x80x9chydroxyl protective groupxe2x80x9d is likewise generally known and refers to groups which are suitable for protecting a hydroxyl group from chemical reactions. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, also alkyl groups, alkyl-, aryl- or aralkylsilyl groups or O,O- or O,S-acetals. The nature and size of the hydroxyl protective groups is not critical because they are removed again after the required chemical reaction or sequence of reactions; preferred groups have 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective groups include aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene or o,p-dimethoxybenzylidene acetal, acyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM). Particularly preferred hydroxyl protective groups are benzyl, acetyl, tert-butyl or TBS.
The liberation of the compounds of the formula I from their functional derivatives is known from the literature for the particular protective group used (for example T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd edition, Wiley, New York 1991 or P. J. Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgartxe2x80x94New York, 1994). It is moreover possible to make use of variants which are known per se but are not detailed here.
The BOC and O-tert-butyl groups can be cleaved off, for example, preferably with TFA in dichloromethane or with approximately 3 to 5N HCl in dioxane in 15-30xc2x0 C., and the Fmoc group with an approximately 5 to 50% strength solution of dimethylamine, diethylamine or piperidine in DMF at 15-30xc2x0 C. The Aloc group can be cleaved under mild conditions with noble metal catalysis in chloroform at 20-30xc2x0 C. A preferred catalyst is tetrakis(triphenylphosphine)palladium(0).
The starting compounds of the formula II to V are usually known. If they are novel, they can, however, be prepared by methods known per se.
Compounds of the formula II are obtained, for example, from coupling the corresponding 2-amino compound of the heterocycle in which Q1, Q2, Q3 or Q4 have the meanings stated in formula I with the appropriate n-bromo carboxylates (Brxe2x80x94[CH2]nxe2x80x94COOPG1, where PG1 is a hydroxyl protective group as described above) n the presence of a base, and subsequently cleaving off the protective group under standard conditions.
Compounds of the formula IV are obtained by a peptide-analogous coupling of compounds of the formula II with a glycine derivative H2Nxe2x80x94CH2xe2x80x94COOPG2, where PG2 is a hydroxyl protective group as described above, under standard conditions.
Compounds of the formula V (xcex2-amino acids) can be prepared in analogy to Skinner et al., J. Org. Chem. 1960, 25, 1756. The reaction of the corresponding aldehyde R3xe2x80x94CHO with malonic acid and ammonium acetate in a suitable solvent, particularly preferably alcohols such as, for example, ethanol, produces the xcex2-amino acid of the formula V where R6 is H. Esterification of this free acid of the formula V under standard conditions affords compounds of the formula V where R6 is A or xe2x80x94(CH2)mxe2x80x94Ar.
Compounds of the formula III are prepared by coupling the xcex2-amino acids of the formula V which are protected on the acid functionality, either by an appropriate protective group or, if R6 is A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar, with a glycine derivative PG3xe2x80x94NHxe2x80x94CH2xe2x80x94COOH. The substituent PG3 in the glycine derivative PG3xe2x80x94NHxe2x80x94CH2xe2x80x94COOH is an amino protective group as described above, which is then cleaved off. Conventional methods of peptide synthesis are described, for example, in Houben-Weyl, l.c. [sic], volume 15/II, 1974, pages 1 to 806.
Compounds of the formula I can be obtained by reacting a compound of the formula II with a compound of the formula III, and then cleaving off a protective group, or converting the radical R6 which is A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar into the radical R6xe2x95x90H.
The compounds of the formula I can likewise be obtained by reacting a compound of the formula IV with a compound of the formula V, and then cleaving off a protective group, or converting the radical R6 which is A, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94C(O)A or xe2x80x94(CH2)mxe2x80x94Ar into the radical R6xe2x95x90H.
The coupling reaction preferably takes place in the presence of a dehydrating agent, for example of a carbodiimide such as dicyclohexylcarbodiimie (DCC), N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrocyhloride (EDC) or diisopropylcarbodiimide (DIC), also, for example, propanephosphonic anhydride (compare Angew. Chem. 1980, 92, 129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents, at temperatures between about xe2x88x9210 and 40, preferably between 0 and 30xc2x0. The reaction time depends on the conditions used and is between a few minutes and several days. It has proved particularly advantageous to add the coupling reagent TBTU (O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate) or O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate, because only a small amount of racemization occurs in the presence of one of these compounds, and no cytotoxic byproducts are formed.
In place of compounds of the formulae II and/or IV, it is also possible to employ derivatives of compounds of the formula II and/or IV, preferably a preactivated carboxylic acid, or a carbonyl halide, a symmetrical or mixed anhydride or an active ester. Residues of this type for activating the carboxyl group in typical acylation reactions are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart). Activated esters are preferably formed in situ, for example by adding HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide.
The reaction normally takes place in an inert solvent and, when a carbonyl halide is used, in the presence of an acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
It may also be beneficial to add an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak acid salt of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium.
A base of the formula I can be converted with an acid into the relevant acid addition salt, for example by reacting equivalent amounts of the base and of the acid in an inert solvent such as ethanol, and then evaporating. Acids particularly suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid, or hydrobromic acid, phosphoric acids such as, for example, ortho-phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, furamic acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and -disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I. On the other hand, compounds of the formula I can be converted with bases (for example sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
The invention also relates to the compounds of the formula I and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.
The invention further relates to compounds of the formula I and their physiologically acceptable salts or solvates as integrin inhibitors.
The invention also relates to the compounds of the formula I and their physiologically acceptable salts or solvates for use for controlling diseases.
The invention further relates to the use of a combination of selective integrin inhibitors selected from the group of selective xcex1vxcex23 integrin inhibitors combined with selective xcex1vxcex26 integrin inhibitors, selective xcex1vxcex25 integrin inhibitors combined with selective xcex1vxcex26 integrin inhibitors or selective xcex1vxcex23 integrin inhibitors combined with selective xcex1vxcex25 integrin inhibitors combined with selective xcex1vxcex26 integrin inhibitors, for producing a pharmaceutical for controlling pathological processes influenced by the integrins xcex1vxcex23 and/or xcex1vxcex25 and xcex1vxcex26.
The invention relates to the use of a combination of selective integrin inhibitors selected from the group of selective xcex1vxcex23 integrin inhibitors combined with selective xcex1vxcex26 integrin inhibitors, selective xcex1vxcex25 integrin inhibitors combined with selective xcex1vxcex26 integrin inhibitors or selective xcex1vxcex23 integrin inhibitors combined with selective xcex1vxcex25 integrin inhibitors and combined with selective xcex1vxcex26 integrin inhibitors, for producing a pharmaceutical for cancer therapy, there being suppression on the one hand of angiogenesis of the blood vessels growing into the tumour through inhibition of the xcex1vxcex23 integrin receptor and/or of the xcex1vxcex25 integrin receptor, and on the other hand of tumor development through inhibition of the xcex1vxcex26 integrin receptor.
The invention relates to the use of a combination of selective xcex1vxcex23 integrin inhibitors and/or selective xcex1vxcex25 and selective xcex1vxcex26 integrin inhibitors for producing a pharmaceutical for controlling diseases associated with cancer, such as metastases of solid tumours, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi""s sarcoma.
Selected compounds of the formula I which are, in particular, selective xcex1vxcex23 and xcex1vxcex26 integrin receptor inhibitors are listed below:
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate.
Selected compounds of the formula I which are, in particular, selective xcex1vxcex25 and xcex1vxcex26 integrin receptor inhibitors are listed below:
a) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
b) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate.
Selected compounds of the formula I which are, in particular, selective xcex1vxcex23, xcex1vxcex25 and xcex1vxcex26 integrin receptor inhibitors are listed below:
a) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
e) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride.
Particularly suitable for use for producing a pharmaceutical for a therapy or for controlling pathological processes which can be influenced by the integrins xcex1vxcex23 and/or xcex1vxcex25 and xcex1vxcex26, in particular for a cancer therapy, as described above, are the integrin inhibitors
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
f) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
g) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
h) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
i) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
j) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
k) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
l) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride.
The invention further relates to the use of selective integrin inhibitors selected from the group of
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
f) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
g) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
h) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
i) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
j) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
k) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
l) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride,
for producing a pharmaceutical for controlling pathological processes influenced by the integrins xcex1vxcex23 and/or xcex1vxcex25 and xcex1vxcex26.
The invention relates to the use of selective integrin inhibitors selected from the group of
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
f) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
g) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
h) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
i) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
j) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
k) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
l) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride,
for producing a pharmaceutical for cancer therapy, there being suppression on the one hand of angiogenesis of the blood vessels growing into the tumour through inhibition of the xcex1vxcex23 integrin receptor and/or of the xcex1vxcex25 integrin receptor, and on the other hand of tumour development through inhibition of the xcex1vxcex26 integrin receptor.
The invention relates to the use of selective xcex1vxcex23 integrin inhibitors and/or selective xcex1vxcex25 and selective xcex1vxcex26 integrin inhibitors selected from the group of
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
f) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
g) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
h) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
i) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
j) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
k) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
l) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride,
for producing a pharmaceutical for controlling diseases which are associated with cancer, such as metastases of solid tumours, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi""s sarcoma.
Particularly suitable for use for producing a pharmaceutical for cancer therapy, there being suppression on the one hand of angiogenesis of the blood vessels growing into the tumour through inhibition of the xcex1vxcex23 integrin receptor, and on the other hand of tumour development through inhibition of the xcex1vxcex26 integrin receptor, are the xcex2-alanine derivatives
a) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-chloro-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(4-methyl-3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-(4-methyl-3-nitrophenyl)-3-{2-[4-(pyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
e) 3-(biphenyl-4-yl)-3-{2-[5-(pyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate.
Particularly suitable for use for producing a pharmaceutical for cancer therapy, there being suppression on the one hand of angiogenesis of the blood vessels growing into the tumour through inhibition of the xcex1vxcex25 integrin receptor, and on the other hand of tumour development through inhibition of the xcex1vxcex26 integrin receptor, are the xcex2-alanine derivatives
a) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
b) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid trifluoroacetate.
Particularly suitable for use for producing a pharmaceutical for cancer therapy, there being suppression on the one hand of angiogenesis of the blood vessels growing into the tumour through inhibition of the xcex1vxcex23 and xcex1vxcex25 integrin receptor, and on the other hand of tumour development through inhibition of the xcex1vxcex26 integrin receptor, are the xcex2-alanine derivatives
a) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-methyl-3-nitrophenyl)propionic acid trifluoroacetate;
b) 3-(3-nitrophenyl)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}propionic acid trifluoroacetate;
c) 3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(4-trifluoromethoxyphenyl)propionic acid trifluoroacetate;
d) 3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}-3-(3-trifluoromethoxyphenyl)propionic acid trifluoroacetate or
e) 3-(3-nitrophenyl)-3-{2-[5-(4-methylpyridin-2-ylamino)pentanoylamino]acetylamino}propionic acid hydrochloride.
Also conceivable in addition to the use according to the invention of the selective integrin receptor inhibitors as internal combination therapy of at least two integrin inhibitors are other combinations with conventional therapies such as radiotherapy, tumour vaccination, immunotherapy or chemotherapy. This combined internal and external therapeutic approach ought to increase the efficacy of the treatment further, in particular reduce the dosage of the toxic therapeutic agents and thus also reduce the dose-related side effects.
The invention further relates to pharmaceutical compositions comprising at least one compounds of the formula I and/or one of its physiologically acceptable salts or solvates, which are produced in particular by nonchemical means. It is possible for this purpose to convert the compounds of the formula I together with at least one solid, liquid and/or semiliquid carrier or excipient and, where appropriate, in combination with one or more other active ingredients into a suitable dosage form.
These compositions can be used as pharmaceuticals in human or veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. Used for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, suspensions or drops, for rectal administration are suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical administration are ointments, creams or dusting powders. The novel compounds can also be lyophilized, and the resulting lyophilisates can be used, for example, for producing products for injection. The stated compositions can be sterilized and/or comprise excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colourants, flavourings and/or a plurality of other active ingredients, for example one or more vitamins. The sprays which can be used for administration as spray for inhalation comprise the active ingredient either dissolved or suspended in a propellant gas or mixture of propellant gases (for examples CO2 or chlorofluorocarbons). In this case, the active ingredient is preferably used in micronized form, it being possible for one or more additional physiologically tolerated solvents to be present, for example ethanol. Solutions for inhalation can be administered using conventional inhalers.
The compounds of the formula I and their physiologically acceptable salts or solvates can be used as integrin inhibitors for controlling diseases, in particular thromboses, myocardial infarct, coronary heart disease, arteriosclerosis, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I according to claim 1 and/or their physiologically acceptable salts are also used for pathological processes which are maintained or propagated by angiogenesis, in particular tumours or rheumatoid arthritis.
Selected compounds of the formula I and/or their solvates, as described above, are used for controlling pathological processes influenced by the integrins xcex1vxcex23 and/or xcex1vxcex25 and xcex1vxcex26, in particular cancer therapy, there being suppression on the one hand of angiogenesis with the blood vessels growing into the tumour through inhibition of the xcex1vxcex23 integrin receptor and/or of the xcex1vxcex25 integrin receptor, and on the other hand of tumour development through inhibition of the xcex1vxcex26 integrin receptor.
In this case, the substances according to the invention are usually administered in analogy to the compounds described in WO 97/26250 or WO 97/24124, preferably in dosages between about 0.05 and 500 mg, in particular between 0.5 and 100 mg, per dose unit. The daily dose is preferably between about 0.01 and 2 mg/kg of body weight. The specific dose for each patient depends, however, on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and mode of administration, on the rate of excretion, medicinal substance combination and severity of the particular disorder for which the therapy is applied. Parenteral administration is preferred.
The compounds of the formula I can also be used as integrin ligands for producing columns for affinity chromatography to prepare pure integrins.
The ligand, that is to say a compound of the formula I, is in this case covalently coupled via an anchor functionality, for example the carboxyl group, to a polymeric support.
Suitable polymeric support materials are the polymeric solid phases known per se in peptide chemistry, which preferably have hydrophilic properties, for example crosslinked polysaccharides such as cellulose, Sepharose or SephadexR, acrylamides, polymers based on polyethylene glycol, or TentakelR polymers.
The materials for the affinity chromatography for purifying integrins are produced under conditions like those customary and known per se for condensing amino acids.
The compounds of the formula I contain one or more chiral centres and can therefore exist in racemic or in optically active form. Racemates which are obtained can be separated into the enantiomers mechanically or chemically by methods known per se. It is preferred to form diastereomers from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as xcex2-camphorsulfonic acid. It is also advantageous to separate the enantiomers using a column packed with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture, for example in the ratio 82:15:3 by volume.
It is, of course, also possible to obtain optically active compounds of the formula I in the methods described above by using starting materials which are already optically active.
All temperatures herebefore and hereinafter are stated in xc2x0 C. In the following examples, xe2x80x9cusual workupxe2x80x9d means: water is added if necessary, the pH is adjusted to between 2 and 10 if necessary, depending on the constitution of the final product, extraction is carried out with ethyl acetate or dichloromethane, and the organic phase is separated off, dried over sodium sulfate, evaporated and purified by chromatography on silica gel, by preparation HPLC and/or by crystallization. The purified compounds are freeze dried where appropriate.
RT=retention time (in minutes) on HPLC in the following systems;
Column:
Lichrosorb RP-18 (5 xcexcm) 250xc3x974 mm;
Lichrosorb RP-18 (15 xcexcm) 250xc3x9750 mm.
The eluents used are gradients of acetonitrile (B) with 0.1% TFA (trifluoroacetic acid) and water (A) with 0.1% TFA. The gradient is stated in percent acetonitrile by volume.
Preferred gradient: 5 min at 20% B and 55 min up to 90% B.
Detection at 225 nm.
The retention times labelled with * were measured with the gradient 5 min at 5% B and 40 min up to 80% B. The compounds purified by preparation HPLC are isolated as trifluoroacetates.
Mass spectrometry (MS) by FAB (fast atom bombardment): MS-FAB (M+H)+.